Rat peripheral nerve components release calcitonin gene-related peptide and prostaglandin E2 in response to noxious stimuli: evidence that nervi nervorum are nociceptors.

The presence of an intrinsic afferent innervation of nerves and their connective tissues (nervi nervorum) suggests that these neural elements participate in sensation and pathological processes affecting nerves. Primary afferent nociceptors contain and release neuropeptides including calcitonin gene-related peptide, implicated in inflammatory vasodilatation. We sought to evaluate the ability of different peripheral nerve components, in vitro, to release calcitonin gene-related peptide and prostaglandin E2 in response to electrical and noxious chemical stimuli, using sensitive enzyme immunoassays. We observed significant increases in both calcitonin gene-related peptide and prostaglandin E2 in response to a mixture of inflammatory mediators (bradykinin, histamine, and serotonin; 10(-5) M) applied to the intact nerves (+37% and +700%, respectively) and isolated sheaths (35% and 430%, respectively), but not when this mixture was applied to isolated axons. Proximal (antidromic) but not distal (orthodromic) electrical stimulation also evoked a comparable release of calcitonin gene-related peptide (+30%) from intact nerves. These results suggest that nervi nervorum nociceptors participate in neural inflammation. Capsaicin (10(-6) M) elicited a very large release of calcitonin gene-related peptide when applied to either the intact nerve (+400%), isolated sheaths (+500%), or isolated axons (1400%). The latter effect was substantially but not completely blocked by Ruthenium Red and capsazepine, and was completely blocked using a calcium-free bathing solution. The results support the presence of capsaicin receptors in peripheral nerves that can effect calcitonin gene-related peptide release from axons as well as from terminals.